This book focuses on novel approach to characterize developmental changes in pharmacokinetics across human lifespan with the up-to-date Nonlinear Mixed Effect Modeling techniques.
The overall goal was to develop individualized dosing guidelines for the sedatives propofol and midazolam in infants and in critically ill patients, on the basis of population pharmacokinetic... Show moreThe overall goal was to develop individualized dosing guidelines for the sedatives propofol and midazolam in infants and in critically ill patients, on the basis of population pharmacokinetic-pharmacodynamic (PK-PD) modeling. Both under- and oversedation significantly and adversely affects patient outcome. Due to the high intra- and interindividual variability in dose requirements dosing is complicated. In this thesis the interindividual variability in response has been examined by covariate analysis. In this analysis the effects of bodyweight, cardiac function, severity of illness and liver blood flow and the unexplained interindividual variability have been characterized. It was shown that infants require higher doses of propofol because of differences in pharmacokinetics rather than pharmacodynamics. When comparing the results of the PK-PD model of propofol and midazolam in infants, propofol is preferred over midazolam because of the lower interindividual variability in pharmacodynamics compared to midazolam. In critically ill patients severity of the illness was found to be a major determinant of the level of sedation, with lower propofol dosing requirements with increasing severity of illness. The PK-PD models can be used as a basis for individualized dosing of propofol and midazolam, which is essential for optimizing the quality of sedation in clinical practice and will improve patients__ outcome. Show less
